Germicidal compositions

ABSTRACT

COMPOSITIONS POSSESSING ANTIBACTERIAL ACTIVITY THROUGH THE USE OF SYNERGISTIC MIXTURE OF HEXACHLOROPHENE, TRICLOCARBAN AND HALOGEN SUBSTITUTED PHENYL 2-ETHYLHEXYL-1UREAS.

March 28, 1972 E. JUNGERMANN ErAL 3,652,767

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INHIBITORY CONCENTRATION) IN PPM Nmd MIC (MIN/MUM l vmd INVENTORS ERICJUNGERMANN DAV/D TABER LEO A. RAPHAEL/AN United States Patent Oflice3,652,767 Patented Mar. 28, 1972 US. Cl. 424-322 4 Claims ABSTRACT OFTHE DISCLOSURE Compositions possessing antibacterial activity throughthe use of a synergistic mixture of hexachlorophene, triclocarban andhalogen substituted phenyl 2-ethylhexyl-1- ureas.

BACKGROUND OF THE INVENTION Antiseptic or antibacterial agents have beenused in soaps and other detergent and cosmetic compositions for aconsiderable period of time. Prior to World War II, the most widely usedmaterials for such purpose were certain cresol derivatives. Althoughthese cresol derivatives were somewhat effective they tended to impart astrong characteristic odor to the soap which severely limited their usein the consumer soap market. In 1941, Kunz and Gump discovered thatcertain halogenated bisphenols maintained their antibacterial activityin the presence of soap without imparting any negative qualities. Thisdiscovery was subsequently patented under U.S. 2,535,077. The mostpromising of the halogenated bisphenols was hexachlorophene[2,2-methylene-bis(3,4,6- trichlorophenol)] and it subsequently becamewidely used in consumer toilet soap products.

Since the discovery by Kunz and Gump, the popularity of antibacterialcleansing compositions such as soap for both laundry and toilet use hasincreased tremendously. It is now estimated that over 46% of allconsumer dollars spent annually in the United States on toilet soap ison antibacterial and deodorant soaps.

Although the past decade has seen major improvements in antibacterialsystems for cleansing compositions such as soap, such as theintroduction of a number of new antibacterial agents and theintroduction of synergistic antibacterial systems, the number ofcompounds and systems that have been developed and which are suitablefrom technical, safety and economic points of view is really quitesmall. In order for an antibacterial agent to become a successfulcandidate for use in a product such as toilet soap, it must possess anumber of properties, such as:

(1) Broad spectrum antibacterial activity in the presence of soap orother cleansing agent.

(2) Substantivity to the skin.

(3) Effective deodorancy.

(4) Efficacy in degerming the skin and in the control of certainbacterially caused skin conditions, such as diaper rash, and secondaryinfections of cuts, scratches and abrasions.

(5) Chemical stability in the presence of the cleansing composition.

(6) Compatibility with the color and odor of the finished product.

(7) Non-reactivity with the other components of the cleansingcomposition, that is, perfumes, antioxidants, brighteners, etc.

(8) Mildness and safety for general use of the finished product.

(9) Satisfactory economics.

Relatively few antibacterial agents or bacteriostats have been found tomeet all of the above requirements. At the present time the mostimportant commercially used bacteriostats for use in cleansingcompositions such as soap.

are hexachlorophene, TCC (triclocarban), TBS (3,4,5-tribromosalicylanilide), and 4,4 dichloro 3 trifluoromethyl carbanilide.While the above compounds have, in general, excellent properties and arewidely used, they all have certain drawbacks. Hexachlorophene issomewhat sensitive to sunlight. The substituted ureas may be unstable inalkali media at elevated temperatures; and, in the case of thehalogenated salicylanilides, there have been instances of isolated casesof photodermatitis.

The most significant advance in soap bacteriostats has been thedevelopment of synergistic bacteriostatic systems. The term synergisticactivity as applied herein means an antibacterial effect which isgreater in combination than the sum of the antibacterial etfects of theseparate components. Casely and Noel in US. Pat. 3,117,155 disclose andclaim synergistic binary antibacterial systems comprising mixtures ofthe isomeric trihalogenated carbanlides with a number of halogenatedbisphenols and alkylated halogenated bisphenols.

A preferred synergistic combination according to the Casely and NoelU.S. Patent 3,177,155 is hexachlorophene and certain of the halogenatedcarbanilides, particularly triclocarban. The discovery of synergismbetween the halogenated bisphenols and the halogenated carbanilides wasextremely important in that it permitted soap manufacturers and othersto provide detergent compositions having a high level of antibacterialactivity, but on the other hand, having a greatly reduced concentrationof antibacterial agents. The discovery was of further importance becauseone could then substantially decrease the amount of hexachloropheneemployed in the antibacterial composition and thereby greatly reduce thetendency of such compositions to discolor upon prolonged exposure tosunlight.

It has been previously found by others that antibacterial properties areimparted to various compositions by the incorporation therein of halogensubstituted phenyl 2-ethylhexyl-1-ureas. In Belgian Pat. 709,240 to CibaSociete Anonyme it is stated that such ureas are eifective broadspectrum antibiotics. The preparation of the aforementioned ureas arefully set forth in this Belgian patent.

SUMMARY OF THE INVENTION In accordance with this invention, it has beenfound that mixtures of [1-(2-ethylhexyl)-3-(3,5-bis (trifluoromethyl)phenyl)urea]and having the structure NHCNHCH2CH( CH2)3CH3 triclocarbanand hexachlorophene exhibit synergistic antibacterial activity and thatthis activity is maintained unimpaired when such mixtures areincorporated into various detergent compositions such as soap and alsoin various cosmetic preparations.

It is therefore an object of this invention to provide antibacterialcompositions which include as antibacterial agents a synergisticcombination of hexachlorophene.

It is a still further object of this invention to provide antibacterialagents which are effective in soap and in other detergent and cosmeticmediums.

Other objects and advantages and a fuller understanding of our inventionwill become apparent from the ensuing description and examples.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In a specific embodiment, ourinvention may be exemplified by a soap composition containing as theactive antibacterial ingredient a synergistic mixture of (A) theaforementioned urea and (B) hexachlorophene [2,2-methylene-bis(3,4,6-trichlorophenol)] and (C) triclocarban and whereinthe ratio of B to C present in the soap in parts by weight is about 1 to1 and wherein the ratio of A to the sum of B plus C is from about 1 to6.7 to about 9.3 to 1.

It is found that when components A, B and C of the synergistic mixtureas set forth above are used together, a germicidal effect is achievedwhich is substantially greater than the mere total of the individualeffects of the individual ingredients. This is important in cases whereit is desirable to increase the activity of the hexachlorophene andtriclocarban ingredients without employing higher concentrations, and inother cases, it assumes an even greater importance from an economicstandpoint, since the presence of the halogen substituted phenyl 2-ethylhexyl-l-urea enables a reduction in the total concentration of theantibacterial agent while at the same time retaining the desired levelof antibacterial elfect.

What the actual mechanism of the potentiating or synergistic effect is,we cannot explain. The invention relates to the synergistic cooperationof these three agents when used in minor proportions in variouscompositions, especially detergent compositions such as soap, and thediscovery that this synergistic phenomenon occurs even at the high pHconditions existing in soap and other detergent formulations.

Relatively small amounts of the components of our synergistic mixtureare sufficient for the increased antibacterial eifect. Satisfactoryresults can be obtained when the combined weights of the above threeagents are from .10% to 5.0% of the total weight of the composition. Apreferred range is the weight concentration of about 1.0% to 2.5%. Itshould be understood that even concentrations below the ranges set outabove will provide some degree of antibacterial effect and asubstantially higher concentration than those referred to will also givesatisfactory results, although there are certain practicalconsiderations such as the cost of the agents Which limits thedesirability of greater amounts of the germicidal composition in thesoap or other medium.

As indicated above, the ratio of the urea to the hexachlorophene plustriclocarban is from about 1 to 6.7 to about 9.3 to 1 (parts by weight).

The term soap refers to the Water-soluble ammonium, metallic, or organicbase salts of various fatty acids, which are chiefly lauric, oleic,stearic, and palmitic acids. As used in this description, the term isintended to cover all products in which soap is a major constituent, forexample, bar, flake, powdered, soft and liquid soaps; shaving creams,toothpaste, cleansing creams, etc.

The anionic type and nonionic type synthetic detergents can be used inplace of the soap. The anionic type synthetics suitable for use in theinvention can be described as those detergents having pronouncedcleansing power and including in their molecular structure an alkylradical containing from 6 to 18 carbon atoms and a sulfonic acid orsulfuric acid ester radical. Either organic base, ammonium, sodium orpotassium salts of the anionic type detergents can be used. The maintypes of detergents falling within this category are alkyl-arylsulfonates, such as sodium or potassium dodecyl benzene sulfonate,sodium or potassium octadecyl benzene sulfonate, and sodium or potassiumoctyl naphthalene sulfonate; the alkyl sulfates, such as sodium orpotassium salts of dodecyl, hexadecyl, and octadecyl sulfates; thesulfonated fatty acid amides, such as sodium or potassium salts of theoleic acid amide of methyl taurine; and the sulfonated monoglyceridessuch as the mono-coconut oil fatty acid ester of sodium1,2-hydroxypropane-3-sulfonate.

The nonionic type synthetic detergents suitable for use in the inventionmay be described as those detergents which do not ionize in solution butowe their watersolubility to unionized polar groups such as oxyethyl orother linkages. The main types of detergents falling within thiscategory are the polyoxyethylene ethers of the higher fatty alcohols andalkyl phenols; the polyethylene glycols of fatty acids; fatty alkylolamide condensation products; polymers of ethylene and propylene oxides;compounds formed by the addition of propylene oxide to ethylene diamine,followed by the addition of ethylene oxide; fatty acid ethylene oxidecondensation products; condensation products of ethylene oxide and afatty acid ester of a polyhydric alcohol or sugar; and the detergentsprepared by heating together a higher fatty acid with a diethanolamine.Some examples of synthetic nonionics suitable for the purpose of thisinvention are ethylene oxide-tall oil fatty acid reaction products;isooctyl phenol-ethylene oxide reaction products; propyleneoxide-ethylene oxide reaction products; and combinations of isooctylphenolethylene oxide with coconut oil fatty acid ethylene oxide reactionproducts.

The synergistic combination of [1-(2 -ethylhexyl) 3-(3,5-bis(trifiuoromethyl) phenyl) urea], triclocarban andhexachlorophene can be added to the soap and other detergents by anysuitable method which results in a uniform distribution of the agentsthroughout the entire mass.

Specific examples illustrating our invention are set out as follows:

EXAMPLE I A convenient and meaningful method of measuring theantibacterial effectiveness of various agents is by means of a modifiedagar streak method utilizing a 10% soap solution (100,000 p.p.m. ofsoap) containing the various test agents. Briefly the test consists ofmaking serial dilutions of the following solution: 10 ml. of a solutioncontaining 0.7% of the urea and 0.3% of equal parts by weight ofhexachlorophene and trichlocarban in dimethylformamide were dispersedinto 80 ml. of distilled water containing 10 grams of soap. Allsolutions are maintained at 60 C. until they are dispensed. Aliquots ofthe dilutions containing concentrations of the bacteriostatic agentsranging from about 0.02 to 10 p.p.m. are dispensed into measured amountsof nutrient agar at 50 C. and thoroughly dispersed. Plates are poured,allowed to solidify and streaked with a standard 4 mm. loopful of a 24-hour broth culture of Staphylococcus aureus FDA 209. After incubationfor 24 hours at 37 C. the bacteriostatic end point is determined. Thebacteriostatic end point, hereinafter called the minimum inhibitoryconcentration (MIC), represents the minimum concentration in p.p.m. ofthe bacteriostatic agent necessary to inhibit all growth of theinnoculent organism. No particular minimum inhibitory concentration hasbeen established to determine the usefulness of a bacteriostatic agent,although the lower the end-point, the better the bacteriostatic activityand the smaller the amount of the agent necessary to maintain aparticular degree of effectiveness. The soap utilized for theseevaulations was a neutral white toilet soap containing about 20% byWeight sodium coco soap and 80% by weight sodium tallow soap.

Using the modified agar streak method as set forth above it wasdetermined that a soap solution containing 0.70% of the[l-(2-ethylhexyl)-3-(3,5-bis(trifluoromethyl)phenyl)urea] had an endpoint or MIC of 0.20 p.p.m. It was also determined that a soap solutioncontaining 0.4% of hexachlorophene and triclocarban (1:1 ratio) had anend point about 0.20 p.p.m. Various proportions of the above solutionswere combined to give mixtures that would be expected to give an endpoint or MIC of 0.20 p.p.m., if no synergistic activity took place. Inthe following table, there is set forth the MIC of varying ratios of thesubstituted urea and hexachlorophene.

Parts of a 1,50% Ratio of substihexachlorophene Percent hexatuted urea lto C plus tri- Percent chlorophene hexaehlorophene (p.p.m.) Parts of a0,70% substituted clocarban substituted plus triplus triversus urea 1solution solution 2 urea. clocarban clocarban S. aureus 100 0. 300 1: on0. 18 98 0. 014 0. 294 1:21. 0 0. 18 96 0. 028 0. 288 1:10. 3 0. 18 940. 042 0. 282 1:6. 7 0. 16-0. 18 90 0. 070 0. 170 1:3. 9 0. 16 80 0. 1400. 240 1:1. 7 0. 16-0. 18 70 0. 210 0. 210 1:1 0. 14-0. 16 60 0. 280 0.180 1. 6:1 0. 16-0. 18 50 0. 350 0. 150 2. 3: 1 0. 14-0. 16 40 0. 420 0.120 3. 6: 1 0. 16-0. 20 30 0. 490 0.090 6. 4:1 0. 16-0. 71) 20 0. 560 0.060 9. 3:1 0. 18 0. 630 0. 030 21. 0:1 0. 0 0. 700 0 m :1 0. 18-0. 24

NOTE.Tested at 0.05, 0.14, 0.16, 0.18, 0.20, 0.22, 0.24, 0.26, and 0.50p.p.m.

The results as set forth in the above table have been reproduced ingraph form on the attached drawing. In the graph the MICs (ordinate)have been plotted against the concentration of the agents in parts byweight. Line A represents the expected MIC if the activity of the threeagents were merely additive. The curved line B represents the actualMICs of a combination of the three agents at varying proportions. Thatportion of line B lying between points C and D represents the region inwhich unexpected or synergistic activity takes place. Thus, there issynergism when the ratio of hexachlorophene to triclocarban is about 1to 1 and when the ratio of the urea to the hexachlorophene plustriclocarban is from about 1 to 6.7 to about 9.3 to 1.

The results set forth in the foregoing example with respect to aspecific soap (20% sodium coco and 80% sodium tallow soap) are obtainedwith soaps generally. Thus, a fatty acid soap such as sodium laurate,potassium stearate, sodium oleate, and potassium myristate will alsoproduce these results. Furthermore, the synergistic action isindependent of the soap medium and will take place in non-detergentmedia as 'well as in anionic detergents other than soap and in nonionicsystems. At the same time, soap is a system in which the synergisticcomponents are highly eifective and useful.

While this invention has been described in and exemplified in terms ofits preferred embodiments, those skilled in the art will appreciate thatvariations can be made without departing from the spirit and scope ofthe invention.

What is claimed is:

1. Antibacterial compositions consisting essentially of a synergisticcombination of hexachlorophene, triclocarban and1-(2-ethylhexyl)-3-(3,5-bis(trifluoromethyl) phenyl)urea [halogensubstituted phenyl Z-ethylhexyl-lurea] wherein the ratio of said urea tosaid hexachlorophene plus said triclocarbon in parts by weight is fromabout 1 to 6.7 to about 9.3 to l and wherein the ratio ofhexachlorophene to triclocarban is about 1 to 1.

2. Antibacterial compositions according to claim 1 wherein the totalconcentration of said hexachlorophene and urea is from about .10% toabout 5.0% by weight of the composition.

3. Antibacterial compositions according to claim 1 which contain acleansing composition selected from the group consisting ofwater-soluble soap, anionic synthetic detergent and nonionic syntheticdetergent.

4. The antibacterial compositions of claim 3 wherein the cleansingcomposition is a water-soluble soap.

References Cited UNITED STATES PATENTS 2,535,077 12/1950 Kunz et a1.252-107 2,818,390 12/1957 Beaver et a1 260-553 3,177,115 4/1965 Caselyet al. 252-107 X OTHER REFERENCES Chem. Absts.-vol. 70, p. 106177y.

HERBERT B. GUYNN, Primary Examiner P. E. WILLIS, Assistant Examiner US.Cl. X.R.

